An antibody-drug conjugate (ADC) having a drug with cytotoxicity conjugated to an antibody which binds to an antigen expressed on a surface of cancer cells and capable of cellular internalization (the antibody which binds to the antigen is also capable of cellular internalization), can deliver the drug selectively to the cancer cells and is thus expected to cause accumulation of the drug in the cancer cells and to kill the cancer cells (see, Non Patent Literatures 1 to 3). As an ADC, Mylotarg (registered trademark; Gemtuzumab ozogamicin) in which calicheamicin is conjugated to an anti-CD33 antibody is approved as a therapeutic agent for acute myeloid leukemia. Further, Adcetris (registered trademark; Brentuximab vedotin), in which auristatin E is conjugated to an anti-CD30 antibody, has recently been approved as a therapeutic agent for Hodgkin's lymphoma and anaplastic large cell lymphoma (see, Non Patent Literature 4). The drugs contained in ADCs which have been approved until now target DNA or tubulin.
As an antitumor, low-molecular-weight compounds, camptothecin derivatives, which inhibit topoisomerase I to exhibit an antitumor effect, are known. Among them, an antitumor compound represented by the formula below (exatecan, chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-10,13(9H,15H)-dione) is a water soluble derivative of camptothecin (Patent Literature 1 and 2).

Unlike irinotecan currently used in clinical settings, this compound does not require activation by an enzyme for exerting its antitumor effect. Further, compared to SN-38 as a main pharmaceutically active ingredient of irinotecan and topotecan also used in clinical settings, it has higher inhibitory activity on topoisomerase I and has higher cytocidal activity in vitro against various cancer cells. In particular, it exhibits the effect against cancer cells which have resistance to SN-38 or the like due to expression of P-glycoprotein. Further, in a mouse model with a human tumor subcutaneously transplanted, it exhibited a potent antitumor effect, and thus has undergone the clinical studies, but has not been put on the market yet (see, Non Patent Literatures 5 to 10). It remains unclear whether or not exatecan functions effectively as an ADC.
DE-310 is a complex in which exatecan is conjugated to a biodegradable carboxymethyldextran polyalcohol polymer via a GGFG peptide spacer (SEQ ID NO: 585) (Patent Literature 3). By making exatecan into a form of a polymer prodrug, a high blood retention property can be maintained and also a high penetration property to a tumor area is passively increased by utilizing the increased permeability of newly formed tumor vessels and retention property in tumor tissues. With DE-310, the peptide spacer is cleaved by an enzyme to continuously release exatecan as a main active ingredient and exatecan with glycine bonded to an amino group, and as a result, the pharmacokinetics are improved. According to various tumor evaluation models in non-clinical studies, it was found that higher effectiveness was obtained by DE-310 than exatecan administered alone even though the total amount of exatecan contained therein is lower than the case of administration of exatecan alone. A clinical study was conducted for DE-310, and effective cases were confirmed. There is also a report suggesting that the main active ingredient accumulates in a tumor than in normal tissues. However, there is also a report indicating that the accumulation of DE-310 and the main active ingredient in a tumor is not much different from the accumulation in normal tissues, and thus no passive targeting is observed in humans (see, Non Patent Literatures 11 to 14). As a result, DE-310 was not also commercialized, and it remains unclear whether or not exatecan effectively functions as a drug oriented for such targeting.
As a compound relating to DE-310, a complex in which a structure moiety represented by —NH—(CH2)4—C(═O)— is inserted between -GGFG-spacer (SEQ ID NO: 585) and exatecan to form -GGFG (SEQ ID NO: 585)-NH—(CH2)4—C(═O)— used as a spacer structure is also known (Patent Literature 4). However, the antitumor effect of the complex is not known at all.
The human epidermal growth factor receptor 3 (also known as HER3 and ErbB3) is a receptor protein tyrosine kinase and belongs to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases, which also includes HER1 (also known EGFR), HER2, and HER4 (see Non Patent Literatures 15 to 17). As with the prototypical epidermal growth factor receptor, the transmembrane receptor HER3 consists of an extracellular ligand-binding domain (ECD), a dimerization domain within the ECD, a transmembrane domain, and a carboxyl-terminal phosphorylation domain. HER1, HER2, and HER4 carry an intracellular protein tyrosine kinase domain (TKD) in addition to these domains, while HER3 lacks this domain and is thus unable to be autophosphorylated.
The ligand Heregulin (HRG) binds to the extracellular domain of HER3 and activates the receptor-mediated signaling pathway by promoting dimerization with other human epidermal growth factor receptor (HER) family members and transphosphorylation of its intracellular domain. The dimer formation of HER3 with other HER family members expands the signaling potential of HER3 and serves as means not only for signal diversification but also for signal amplification. For example, the HER2/HER3 heterodimer induces one of the most important mitogenic signals among HER family members. HER3 is overexpressed in several types of cancers such as breast, gastrointestinal, and pancreatic cancers. Interestingly, a correlation between the expression of HER2/HER3 and the progression from a non-invasive stage to an invasive stage has been shown (see Non Patent Literatures 18 to 20). Accordingly, agents that interfere with HER3-mediated signaling are desirable. Anti-HER3 antibodies and immunoconjugates thereof have been reported in, for example, Patent Literatures 5 to 10, respectively.